Chronic kidney disease (CKD) is a growing public health problem that currently affects more than 500 million people worldwide. Given the growth of major risk factors, including obesity, hypertension and diabetes mellitus (DM), the prevalence of CKD and its consequences will continue to expand. In addition to the risk of progressing to end stage renal disease, patients with CKD suffer from premature death due to cardiovascular disease (CVD). The mortality rates in advanced CKD are six times higher than the Medicare population. Emerging data over the past decade suggest a critical role of non-traditional risk factors in the pathogenesis of CVD. These risk factors include obesity and insulin resistance (IR)-two elements not currently targeted by standard therapies. A significant knowledge gap exists detailing the main determinants of IR in this population, how to optimally characterize this derangement, and whether it can be effectively modified to improve outcomes in this population. The pathophysiology of insulin resistance in CKD is unique. In addition to a high prevalence of obesity (nearly 50%), patients with CKD have important metabolic derangements, such as decreased clearance of insulin and adipokines, metabolic acidosis, and chronic inflammation, that modify the pathophysiology of insulin resistance. Adipose tissue is an endocrine organ that secretes adipokines which include, but are not limited to, adiponectin and leptin.6 These two adipokines have opposing actions. Adiponectin is a key insulin sensitizing hormone with anti-atherogenic effects. In contrast, leptin is atherogenic and promotes insulin resistance. Leptin to adiponectin ratio (LAR) has been proposed as an atherogenic index in diabetes and has been shown to be a sensitive marker of metabolic syndrome. Furthermore, LAR has been shown to be the best correlate of IR in end stage renal disease patients. Given the high prevalence of obesity and metabolic derangements associated with CKD, detailing the interaction between these two conditions and their effect on CV risk is critical. The overarching aim of this proposal is to understand the effect of these interactions on adipokine imbalances and the generation of insulin resistance, and the combination of these effects on vascular health. Novel biomarkers, including imbalances in adipokine profiles, will be tested for their ability to risk stratify patiets. Finally, interventions directed at adipokine dysregulation and insulin resistance will be tested fo its ability to reverse this high risk profile in patients with moderate CKD. Our specific aims are s follows: 1) To characterize the metabolic disturbances that arise from the intersection of increased adiposity and decreased clearance of insulin and adipokines in obese patients with moderate CKD, 1a) To compare the extent of IR using hyperinsulinemic euglycemic clamp (HEGC) studies between patients with and without CKD and the degree to which this is modified by obesity, 1b) To examine if LAR will more appropriately reflect the metabolic state of obesity in the setting of moderate CKD compared to conventional measures of insulin resistance validated against HEGC, 1c) To determine if LAR is a determinant of inflammation, endothelial function, oxidative stress and atherosclerosis in the setting of obesity in CKD; 2) To study the effects of metformin, an AMP-K activator, on the metabolic disturbances associated with CKD and obesity, i.e. insulin resistance, systemic inflammation and oxidative stress, 2a) To test if metformin will improve LAR in obese CKD patients compared to placebo, 2b) To test if metformin will improve markers of systemic inflammation, oxidative stress and endothelial function in this population compared to placebo. 2c) To test if metformin will improve atherosclerosis markers and reduce clinical CVD events in obese patients with moderate CKD compared to placebo. Our proposed studies could potentially impact clinical practice, by providing new monitoring tools and potential targets for intervention to reduce CV mortality in CKD patients. Our study results could have a great impact on VETERANS HEALTH CARE and contribute to the research mission of the Department of Veterans Health administration by improving the care we provide to veteran patients with CKD.